Abstract-Chronic treatment of saline-drmkmg stroke-prone spontaneously hypertensive rats (SHRSP) with agents that interfere with the formation or actions of angotensm II (Ang II) prevents the development of stroke and renal vascular damage Ang II, m addltlon to its direct vascular effects, stimulates the synthesis and release of aldosteroneTo assess the role of aldosterone m the development of pathologc changes m these rats, we implanted time-release pellets containing 200 mg of the mmeralocortlcold receptor antagomst, spu-onolactone, mto 14 SHRSP at 7 5 weeks of age Eight SHRSP httermates received placebo pellets Over the period of study (3 to 4 weeks), systolic blood pressure (SBP) (PRA) and aldosterone as independent nsk factors for heart attack and stroke ' They found that among the patients who developed strokes and myocardlal mfarctlons, all had normal or high PRA, and aldosterone secretlon Previous studies by our group and others have provided expenmental evidence to support a role for the renm-angotensm-aldosterone system (RAAS) m the development of vascular qury, as angotensm converting enzyme (ACE) mhlbltors2-6 and Ang II receptor antagonlsts7-9 prevented the development of stroke and malignant nephrosclerosls m SHRSP Since these studies were conducted m salt-loaded SHRSP, which respond to these agents with nummal blood pressure lowermg, they provided evidence for a pathophyslolog& role for Ang II m the development of vascular lesions of malignant nephrosclerosls independent of severely elevated blood pressure Consistent with a role for Ang II was the finding that SHRSP display a paradoxical increase m PRA with rime, despite continued salt-loading 3 9,'" Although Ang II stimulates the synthesis and release of aldosterone," " m addmon to its direct vascular actions, a role for mmeralocortlcolds m the pathology of SHRSP

Heterogeneous nuclear ribonucleoproteins (hnRNPs) comprise a family of RNA-binding proteins. The complexity and diversity associated with the hnRNPs render them multifunctional, involved not only in processing heterogeneous nuclear RNAs (hnRNAs) into mature mRNAs, but also acting as trans-factors in regulating gene expression. Heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1), a subgroup of hnRNPs, is a KH-triple repeat containing RNA-binding protein. It is encoded by an intronless gene arising from hnRNP E2 through a retrotransposition event. hnRNP E1 is ubiquitously expressed and functions in regulating major steps of gene expression, including pre-mRNA processing, mRNA stability, and translation. Given its wide-ranging functions in the nucleus and cytoplasm and interaction with multiple proteins, we propose a posttranscriptional regulon model that explains hnRNP E1's widespread functional diversity.

Abstract-Stroke-prone spontaneously hypertensive rats (SHRSP) on 1% NaCl drinking solution and Stroke-Prone Rodent Diet develop severe hypertension and glomerular and vascular lesions characteristic of thrombotic microangiopathy seen in malignant nephrosclerosis. We recently reported that spironolactone, a mineralocorticoid receptor antagonist, markedly reduced proteinuria and malignant nephrosclerotic lesions in these animals. This observation, together with our previous findings that angiotensin-converting enzyme inhibitors prevent the development of vascular damage, suggests that mineralocorticoids, as part of the renin-angiotensin-aldosterone system, play a pathophysiological role in this model. In the present study, we examined whether chronic (2-week) infusion of aldosterone can reverse the renal vascular protective effects of captopril in SHRSP. SHRSP received vehicle (nϭ8); captopril alone (50 mg ⅐ kg; or captopril and aldosterone at 20 (nϭ6) or. Systolic blood pressure was markedly elevated in all groups. Vehicle-and aldosterone-infused SHRSP developed severe proteinuria and comparable degrees of renal injury (21Ϯ3% and 29Ϯ3%, respectively) manifested as thrombotic and proliferative lesions in the arterioles and glomeruli. Captopril treatment reduced plasma aldosterone levels concomitant with marked reductions in proteinuria and the absence of histologic lesions of malignant nephrosclerosis. Aldosterone substitution at 20 or 40 g ⅐ kg Ϫ1 ⅐ d Ϫ1 in captopril-treated SHRSP resulted in the development of severe renal lesions (16Ϯ3% and 21Ϯ2%, respectively) and proteinuria comparable with that observed in SHRSP given either aldosterone or vehicle alone. These findings support a major role for aldosterone in the development of malignant nephrosclerosis in saline-drinking SHRSP, independent of the effects of blood pressure. Key Words: hypertension Ⅲ kidney Ⅲ malignant nephrosclerosis Ⅲ captopril Ⅲ aldosterone T he participation of the renin-angiotensin-aldosterone system (RAAS) in the development of hypertensive vascular injury has been widely demonstrated. 1 Numerous studies with angiotensin-converting enzyme (ACE) inhibitors and with angiotensin (Ang) II receptor antagonists have clearly identified Ang II as a major factor responsible for the development of end-organ damage in hypertensive vascular disease. However, mineralocorticoids may also play an important role, because animals with deoxycorticosterone acetate (DOCA)-salt hypertension typically develop severe vascular pathology, and resultant malignant nephrosclerosis, myocardial necrosis, and stroke, 2-5 despite low levels of plasma renin activity. 2,5,6 The renal lesions that develop in DOCA-salt hypertensive rats are characterized by fibrinoid necrosis of blood vessels and proliferative arteriopathy 2-4 and are very similar to those seen in stroke-prone spontaneously hypertensive rats (SHRSP) receiving a high sodium chloride diet 7-11 and in rats with Ang II-salt-induced hypertension. 12 We have shown that chronic administration of agents that inter...

Although circular RNAs (circRNAs) are enriched in the mammalian brain, very little is known about their potential involvement in brain function and psychiatric disease. Here, we show that circHomer1a, a neuronal-enriched circRNA abundantly expressed in the frontal cortex, derived from Homer protein homolog 1 (HOMER1), is significantly reduced in both the prefrontal cortex (PFC) and induced pluripotent stem cell-derived neuronal cultures from patients with schizophrenia (SCZ) and bipolar disorder (BD). Moreover, alterations in circHomer1a were positively associated with the age of onset of SCZ in both the dorsolateral prefrontal cortex (DLPFC) and orbitofrontal cortex (OFC). No correlations between the age of onset of SCZ and linear HOMER1 mRNA were observed, whose expression was mostly unaltered in BD and SCZ postmortem brain. Using in vivo circRNA-specific knockdown of circHomer1a in mouse PFC, we show that it modulates the expression of numerous alternative mRNA transcripts from genes involved in synaptic plasticity and psychiatric disease. Intriguingly, in vivo circHomer1a knockdown in mouse OFC resulted in specific deficits in OFCmediated cognitive flexibility. Lastly, we demonstrate that the neuronal RNA-binding protein HuD binds to circHomer1a and can influence its synaptic expression in the frontal cortex. Collectively, our data uncover a novel psychiatric diseaseassociated circRNA that regulates synaptic gene expression and cognitive flexibility.

Mitochondrial biogenesis is involved in the control of cell metabolism, signal transduction, and regulation of mitochondrial reactive oxygen species (ROS) production. Despite the central role of mitochondria in cellular aging and endothelial physiology, there are no studies extant investigating age-related alterations in mitochondrial biogenesis in blood vessels. Electronmicroscopy and confocal microscopy (en face Mitotracker staining) revealed that in aortas of F344 rats, a decline in mitochondrial biogenesis occurs with aging. In aged vessels, the expression of the mitochondrial biogenesis factors (including mitochondrial transcription factor A and peroxisome proliferator-activated receptor-gamma coactivator-1) was decreased. The vascular expression of complex I, III, and IV significantly declined with age, whereas aging did not alter the expression of complex II and V. Cytochrome c oxidase (COX) expression/activity exhibited the greatest age-related decline, which was associated with increased mitochondrial ROS production in the aged vessels. In cultured coronary arterial endothelial cells, a partial knockdown of COX significantly increased mitochondrial ROS production. In conclusion, vascular aging is characterized by a decline in mitochondrial mass in the endothelial cells and an altered expression of components of the mitochondrial electron transport chain likely due to a dysregulation of mitochondrial biogenesis factors. We posit that impaired mitochondrial biogenesis and downregulation of COX may contribute to the increased mitochondrial oxidative stress in aged endothelial cells.